17alpha-(1-alkynyl)-and 17alpha-(1-alkenyl)-estra-2, 5(10)-dien-17beta-ols and esters corresponding



States Patent 2,944,068 I Paientecl J 916i) ice 7 molecular equivalentof hydrogen in the presence. of a 5% lla-(l-ALKYNYD- ANDival-Annnmynsrun- 2,5()-DIEN-17}8-0LS AND, SPONDING William F. Johns,Morton Grove, llL, assigu'or to G, Searle & 00., Chicago, 111., acorporationof Delaware No Drawing. Filed Mar. 24, 1959',- Ser. No.801,443 7 Claims. c1. 260 397.s

ESTERS CORRE- The present invention relates to steroids in which' the Aring possesses a diene structure and, more particularly, to 17-(l-alkynyl)- and 17-( l-alkenyl)-estra-2,5 10) -dien- 175-015 and theesters derived therefrom. a

The compounds of this invention are represented by the structuralformula wherein X is selected from the group consisting of hy-. drogenand lower alkanoyl radicals and R is selected from the group consistingof lower l-alkynyl and: lower l-alkenyl radicals. The radicalswhich arecomprehended by the term lower alkanoyl are, fo'r'exainple, formyl,

. :acetyl, propionyl, butyryl, valer'yl', caproyhflenanthyl,

caprylyl, and thebranched-chain isomers thereof; said serumconcentration of cholesterol and the correspondingcholestrolzphospholipid ratio without at the producing the potent sideeffects characteristic of groups being the acyl radicals or the alkanoicacids containing less than 9 carbon atoms. Lower l-alk'ynyl radicalsrepresented by Rare; .fo'r exarnple, ethynyl, propynyl, l-butynyl,l-pentyuyl, l-hexynyl, l-heptynyl, l-octynyl and the branched-chainisomersithereof. The term lower l-alkenyl encompasses, for example,vinyl, l-propenyl, 1- butenyl, l-pentenyl, l-hexenyl, l-lieptenyl,l-octenyl, and the branched-chain isomers thereof 1.

An intermediate, estra-2,5(-10) dien-17-one, in the preparation of thecompounds of this invention .CHII'TEB' prepared by a 3-step process fromestr-5(.10).-en-3, 1-7- dione. A methanol; solution ofthe latterdiketoneiis re duced with an aqueous solution of sodium borohydrid e; to'afiord estr-S 10)-en-3B-ol-17:one. Reaction of the latter substance inpyridine with p-toluenesulfonyl chloride yields3B4p-toly1sulfonyloxy)estra5(l0) en-l7-one. Upon treatment of the latterester with activated alkaline aluminum oxide, estra-2g5(10)-dien-l7-oneis obtained.

The 17 x(l-alkynyl)estra-2,5(10)-dien 17fi-ols. of .the presentinvention can be prepared by reaction of the aforementiondtestra-ZjSl0)-dien-l7-on-'withacetylene or an alkyl acetylene in the presence ofanallga'l ine'catalyst. As a specific example, estra-2,5(l0)-dien-l7 oneitreated with acetylene and potassium tertiaryrpentoxideinaTte'rtiary-amyl alcohol solution containingiether, to yield,17dethynylestra-2,5(10)-dien-175-ol] inwention can be prepared bypartial catalytic hydrogenation of the aforementionedl7-(1-alkynyl)estra-2,5 10)- -dien-l7fl-ols. This hydrogenation isaccomplished by treating the latter acetylenic compounds with onemolecu- 'lar equivalent of hydrogen in the presence of a hydrogenationcatalyst. For example, the above-disclosed17aethynylestra-2,5(10)-dien-17,6-ol is reacted with one.

estrogens adapted to regulation of cholestrol metabolism; The inventionwill appear more fully from the examples; which follow. These examplesare set forth by way of illustration only and it will be understood thatthe invention is not to be construed as limited in spirit or in cene; bythe details contained therein as many modifications in materials andmethods will be apparent from this dis closure to those skilled in theIn these examples temperatures are given in degrees centigrade C.).Quantities of materials are expressed in parts by weight unlessotherwise noted.

EXAMPLE 1 Estr-5 (1 0) -en3,B-0l-17-0ne To a solution of 165 parts ofestr-5(10) -ene-3,17-d' he in 3200 parts of methanol is added, at 10159, a solu v of 6.2 parts of sodium borohydride in 150 parts of wet andthe mixture is stirred for 45 minutes. The reaction mixture is treatedwith parts of acetic acid and the resultant solution poured intoSOOO'parts of water. The

resultant-precipitate is collected by filtration} washed withi water,diied; and dissolved .in'benzene. Chromatography of the benzene solutionon l7QQ parts of silica gel? 'fdl lowed by elution with a 10%ethyl"acetate-% benzene solution and recrystallization iron;acetone-petroleum. ether. a t ear- (.1 6 fi-alrllna M-B.-. 1Z:. [cl j{27Its. infr -recl absorption spectrum. p os; s'e'sses'maxima at'2.7.6 and5.77 microns, EXAMPLE- 2 3f3-(p-i'olylsulfonyloxy)estr-5(10) eri-l7 oneY fret solution of 16.8 parts of estr-5(10) en-3l3 ol-17 one inZOO partsof pyridine is added, at 5, 18 p-toluenesulfonyl chloride. The resultantsolution 15 I lowed to stand at room temperature for ls jhours, thentreated with excess aqueous sodium bicarbonate. The rr'iixtur-e isextracted with benzene and thelbenzene soly tionwashed successively withdilute hydroch oric acid, water, aqueous sodium bicarbonate, andwa r;driedoye ranhydrous magnesium sulfate and evaporated todryn invacuo.Recrystallization ofthe residue f rorn meth yields 3 B(p-toly1sulforiylox y) esngs (-1 CI j -en-l7 one, '-137; [u] 5=+l82?. It ppssesses maxima in the infrared at 5.76 and 6.28 microns.

EXAMPLE 3 Ema-2,5610 aim-Hone A solution of 21.2 parts of3fl-(p-tolylsulfonyloxy)- estr-5( 10)-en-17 one in 880 parts of benzeneis passed over a column of 200 parts of activated alkaline aluminumoxide. This aluminum oxide has been activated according to the proceduredescribed by Brockmann and Schodder (B. 74, 73 (1941)). Elution of thecolumn with 880 parts of benzene, removal of the solvent, andrecrystallization of the residue from methanol results in I in theinfrared;

V V V 17g qcetoxy-l7u-(l -propynyljestra-2,5 (10) -diene A, mixture ofparts of'17e-(1-propyny1)estra-2,5(10)- 2,881,188

mum in the infrared at 5.75 microns.

V EXAMPLEfl' V jZn-ethyInyIestra-Z J() dieri-Ufi-ol andg33partsbftertiary-amyl alcohol until the metal is 1 completely dissolved-JThe solution is co'oled'by means of anjce bath, diluted'with parts'ofether, and treated.

with-a rapid stream of acetylene for a period of 15 min-' utes. Tothe'stirred solution is added 2 parts of estra 2,5 (10)-dien-17-pneandthe resultant mixture is treated 'with a slow stream of acetylene, at5 for 6 hours, The

i reaction rnixtureis'allowed to stand at 5 for 18 hours,

7 then neutralized with 100 parts of saturated aqueousam-T monium'chloride. The resultant mixture is extracted with benzene andthebenzeneextract washed successively with water and dilute hydrochloricacid; dried over anhydrous magnesiumsulfate'; and evaporated to drynessunder reduced pressure. The residue is adsorbed on a silicagelchromatographic column and eluted with a 70% benzenepetroleumethersolution. The solvent is' evaporated and the crude productrecrystallized from petroleum ether to afiord 17a-ethynylestra-2,510)-dien-l7fl-ol, M.P.' 98- 98.5;* [a] =|1.3.. Its infrared absorptionspectrum possesses maximaat 2.81,-2.95 and 3.03 microns.

(1 0) -di en-17 one, Mr. 133-134 It has a maxi- Q A potassiumtertiary-pentoxidesolutionis prepared; by: j heating at reflux a mixtureof 3'par1s of potassium metal -dien -17,8-ol, 2 00 pa s-ofacetic-anhydride and 400 parts I ether solution to afford17B-a'cetoxy-17u-(1-propynyl)-' estra'-2;5(l0)'-dierieii substancepossesseiniaxi-niainl' the' infrared 'at'330,355,582, 8.80,and-10.60microhs. j

A mixture of 5 parts of estra -2,5(10)-dien-17-one in V .300 parts ofliquid ammonia and 2 parts of sodamide is saturated with propyne. Thestirred mixture is treated. with a steady stream of propyne for 4 hours,then neutralized with 10 parts of saturated ammonium chloride solution.7 The ammonia is allowed to evaporate and the residue'is mixedwith'benzene and 'water. The organic layer is, separated, washedwithwater, dried over anhys dr ousmagnesium sulfate, and evaporated todryness in vacuo. Chromatography on silica gel afiords 17d. (1; Ipropynyl') -estra-2 ,5 10 dien17,8-ol which possesses maxat 2.83,: 3.30,3.55;8.80;-and 10.59

. "'EXAr MPLE e V 17 irgy r -ast1o)wen-17 I "mixtureiof 5.6 parts of17m-ethynylestra-2,5: (i1 0i:

'dien-1 7fl-ol,2.8 partsof 5% palladium-on -calciumfcar; bonate'catalystand 3.00;parts.of pyridine is stirred :in a

Q hydrogen atmosphere until onelmolecular equivalent of hydrogenis-absorbed. rThe catalyst is removed by filtra; tion, and the filtrateevaporated 'to dryness'at reduced ether solution, and recrystallizationfrom aqueous 'metli anol' to afford 17a-vinylestra-2,5(10)-dien-17fl-ol,M'.P.i 106- 108"; [a] =]'117. IteXhibits maxima in the infrared at2:68,'2.97, and 6.08 microns. I 7

By substituting 17 (1-propyny1):estra-2,5 10) dien- 175-61 and otherwiseproceeding according 'to the herein described processes,17u-(1-propenyl) estra -2,5 (10)-dien-f ljlfl-ol isobtainedi Itsinfrared absorption spectrum posr;

sessesmaxima alt 2.96, 3. 30, 3.55, 8.180, and l0.5 9 microns.'

" EXAMPLE 7':

a and 10.60 microns.

7 at 330,3.55, 5.82, 8.80, and 10.60niicrons. V

7 By substituting 17a-vinylestra-2,5 (10) men-17am, "171xethynylestra-2,5 (10)-dien-l7fi-ol, or l7a-( 1-propenyl).-; estr-: 2,5(10) -dien-17fl.-ol, and otherwise proceeding ac cording to the hereindescribed processes, l7fi-acetoxy 17a-vinylestra-2,5 10) -diene, 17B-acetoxy-l7 oc-ethynylestra-2,5(10)-dien'e, and I Y 17B-acetoxy-17a-(1-propenyl)- estra-2,5(10)-diene' are obtained. The infrared spectra.

of the latter three products possess maxirna 'at. 3.30, 3.55,

3.55, 5,78, 8.80, and l0.60 rnic rons, respectively.

- EXAMPLE'8 1 I7B-butyroxy-17ob vinylestm 2,5 (10 -dien A mixture of 1part of 17avinylestra- 2,5(10)-them 175-01, 35' parts of butyricanhydride, and parts of pyridine is heated on a steam bath for 5 hours.The

7 reaction mixture is cooled, diluted with water, and the resultantmixture extracted with benzene. The benzene residue is purified by meansofchromatography on silica nesium sulfate, and evaporated to dryness invacuo. 'Th'e gel to yield 17/3 butyroxy-17u vinylestra-2,5 (10)-dienewhich exhibit-s maxima in the infrared at 3.30, 3.55, 8.80 Bysubstituting lra-eth n iesim-zjn10 -dimmed and otherwise proceedingaccording ,to the herein de scribed processes17fi-butyroxy-17a-ethynylestra-2,5'(10)- diene is obtained. It possessesmaxima in theinfraredf whatisclaimedisz p 1,,, la,compoundiofthe sctural formula;

V wherein Xiisfselected froin'the group consisting of hy-{ i 7 Ipressure. The residue, is purified by chromatography on Y silica gel,e1ution with a 70% benzene-30% petroleum drogen and lower alkanoylradicals and R is selected from nylradicalsJ V, 2 17a'-ethyny1estra-2,5l0) dien-17/8-0l.

. 17 cc-( l-propynyl) estra-2',5 10) -dien- 17 8-01.

. 1 7a-(1-pr0penyl) estra-2,5( 10) -dien- 17B-ol. 17fi-acetoxy-17vinylestra-2,5 l 0) -'diene.. l7fi-acetoxy-17a ethynylestra-2,5 10)-d,ie'ne.

References Cited in thefil e of; this :patent ;f UNITED srarnsPATENTSTT-V". 2,729,654 couo'n'; ;Jan. 3,1956

5.78, and 6,08; 3.03,.330, 355, 5 .7 8, and 8.80;land 3.30;

: Babcock etial. n,Apr.,7, 1959'

1. A COMPOUND OF THE STRUCTURAL FORMULA